title: Combination of sunitinib with anti-tumor vaccination inhibits T cell priming and requires careful scheduling to achieve productive immunotherapy.
abstract: Sunitinib, a protein tyrosine kinase inhibitor is the frontline therapy for renal and gastrointestinal cancers. We hypothesized that by virtue of its well documented tumor apoptosis and immune adjuvant properties, combination of Sunitinib with anti-tumor immunotherapeutics will provide synergistic inhibition of tumor growth. Our study was designed to evaluate the impact of Sunitinib on immunotherapy mediated anti-tumor immune responses and evaluate its efficacy as a combinatorial therapy with tumor targeted immunotherapeutic vaccination. Mice immunized with recombinant α-lactalbumin, a lactation protein expressed on majority of breast tumors were treated with 1 mg of Sunitinib for seven consecutive days beginning (1) concurrently, on the day of α-lactalbumin immunization or (2) sequentially, on day 9 after immunization. Ten-day lymph nodes or 21 day spleens were tested by ELISPOT assays and flow cytometry to evaluate responsiveness to α-lactalbumin immunization in presence of Sunitinib and distribution of cells involved in T cell antigen priming and proliferation in different lymphoid compartments. In addition, therapeutic efficacy of the α-lactalbumin/ Sunitinib combination was evaluated by monitoring tumor growth in the 4T1 transplanted tumor model. Our studies reveal that concurrent administration of Sunitinib with active vaccination against a targeted tumor antigen inhibits priming to the immunogen due to a drastic decrease in CD11b+CD11c+ antigen presenting cells, leading to failure of vaccination. However, sequential delivery of Sunitinib timed to avoid the priming phase of vaccination results in the desired vaccination mediated boost in immune responses.
authors.affiliation: Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH.
authors.forename: Ritika
authors.initials: R
authors.lastname: Jaini
authors.forename: Patricia
authors.initials: P
authors.lastname: Rayman
authors.forename: Peter A
authors.initials: PA
authors.lastname: Cohen
authors.forename: James H
authors.initials: JH
authors.lastname: Finke
authors.forename: Vincent K
authors.initials: VK
authors.lastname: Tuohy
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D000938:Antigen-Presenting Cells / Q000187:drug effects / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D018450:Disease Progression; D005260:Female; D007167:Immunotherapy / Q000379:methods; D007211:Indoles / Q000494:pharmacology*; D007768:Lactalbumin / Q000276:immunology*; D008198:Lymph Nodes / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D011758:Pyrroles / Q000494:pharmacology*; D013154:Spleen / Q000187:drug effects / Q000276:immunology; D000077210:Sunitinib; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology*; D014611:Vaccination / Q000379:methods
chemical_list: D000276:Adjuvants, Immunologic; D019496:Cancer Vaccines; D007211:Indoles; D011758:Pyrroles; D007768:Lactalbumin; D000077210:Sunitinib
keywords: alpha lactalbumin; dendritic cells; immunotherapy; priming inhibition; sunitinib